The focus of this proposal is on determining the role of autophagy in the selective clearance of pathological tau and the role of the Nrf2 pathway in regulating this process. We will also be exploring potential therapeutic strategies to both increase the clearance of pathological tau and protect against cellular dysfunction caused by toxic forms of tau. In Alzheimer disease (AD) brain tau is abnormally truncated at Asp421 (tau-C), as well as being abnormally phosphorylated, and both of these modifications likely facilitate the formation of toxic conformations that result in compromised neuronal function. Therefore strategies that result in selective clearance of these pathological forms of tau may provide a potential therapeutic approach for the treatment of AD. Previously we provided evidence that full length-tau is preferentially degraded by the proteasome, while tau-C is cleared predominantly by macroautophagy. There are also findings suggesting that tau phosphorylated at Ser262/356 may be preferentially degraded through the autophagy pathway, and there is evidence that the autophagy system may be compromised in AD brain which could be a contributing factor to the accumulation of pathological forms of tau. The Nrf2 pathway plays a central role in regulating the expression of cell survival genes. Nrf2 is activated by oxidative stress, as well as other stressors, which results in the expression of cytoprotective genes, including proteins involved in the autophagy pathway. We found that basal Nrf2 activity is lower in cells expressing tau-C compared to cells expressing full-length tau; however Nrf2 can still be significantly activated in the tau-C cells. In preliminary experiments we found that activation of the Nrf2 pathway resulted in decreased levels of tau-C but not of full-length tau, suggesting an activation of autophagy. Intriguingly, we also found that in Nrf2-/- mice there was an accumulation of abnormally phosphorylated tau, as well as insoluble tau species. In AD brain nuclear Nrf2 levels are decreased, and expression of exogenous Nrf2 or activation of the Nrf2 pathway in AD mouse models attenuates learning deficits. Considering these and other studies our overall hypothesis is that pathologically modified forms of tau are preferentially degraded by autophagy, and that activation of the Nrf2 pathway is likely to have beneficial effects in AD in part by facilitating the degradation of pathological forms of tau. The specific aims of this proposal are t test the following hypotheses: 1. That specific pathological forms of tau are preferentially targeted to the autophagy pathway for degradation. 2. That the Nrf2 pathway plays a role in facilitating the degradation of pathological forms of tau. 3. That activation of the Nrf2 or autophagy pathway results in increased survival of cells that express pathological forms of tau. PUBLIC HEALTH RELEVANCE: Alzheimer disease is the most common cause of older age onset dementia. In the Alzheimer disease brain pathological changes in the tau protein are central to the disease process. There is increasing evidence that physiological and pathological forms of tau may be differentially cleared by the cell. Recent studies from our lab and others have suggested that certainly abnormally phosphorylated and/or cleaved forms of tau are preferentially cleared by autophagy. In addition there is evidence to suggest that in Alzheimer disease autophagic processes may be impaired. Thus, pharmacological interventions that selectively upregulate autophagy and/or target pathological forms of tau to autophagy pathway have the potential of being therapeutically beneficial for treating Alzheimer disease.